Is Empagliflozin equivalent and/or synergistic with ACE inhibition in the prevention of chemotherapy mediated cardiotoxicity?

Abstract

Background: Breast cancer is a major public health concern in Canada. Doxorubicin and Trastuzumab (DOX+TRZ) are two of the most common anti-cancer drugs used in the treatment of breast cancer. While these two anti-cancer drugs improve overall survival in women with breast cancer, they increase the risk of developing heart failure. Several randomized controlled trials have demonstrated that sodium-glucose co-transporter 2 (SGLT2) inhibitors, including Empagliflozin (EMPA), which is a novel anti-diabetic medication, reduce the risk of heart failure associated hospitalization and mortality in patients with and without diabetes. Little is known, however, about whether SGLT2 inhibitors are cardioprotective in the setting of chemotherapy mediated cardiotoxicity. Objective: The specific aim of this thesis is to evaluate whether the prophylactic use of SGLT2 inhibition with EMPA will be comparable and/or synergistic to standard pharmacological therapy using the renin-angiotensin system (RAS) antagonist perindopril (PER) in preventing DOX+TRZ mediated cardiotoxicity in a chronic in vivo female murine model. Methods: In a chronic in vivo murine model of chemotherapy mediated cardiotoxicity, a total of 160 C57Bl/6 female mice received prophylactic treatment with PER (3 mg/kg), EMPA (10 mg/kg), or EMPA+PER orally for a total of 3 weeks as a run-in period prior to weekly administration of DOX+TRZ (8 mg/kg and 3 mg/kg, respectively) intraperitoneally for an additional 3 weeks (total of 6 weeks). Serial echocardiography was performed on a weekly basis and at the end of week 6, cardiac tissue was collected for histological, biochemical, and lipidomic analyses. Results: In mice treated with DOX+TRZ, the left ventricular ejection fraction (LVEF) decreased from 75±3% at baseline to 41±4% at week 6. Prophylactic treatment with either PER, EMPA, or EMPA+PER improved LVEF to 57±3%, 66±3%, and 68±4% at week 6, respectively (p<0.05). Histological analyses confirmed significant disruption of myofibrils, vacuolization, and loss of sarcomere integrity in the DOX+TRZ treated mice. Prophylactic administration with PER, EMPA, or EMPA+PER, however, improved myofibril integrity at week 6 in mice receiving DOX+TRZ. Additionally, the Bax/Bcl-xL ratio was significantly elevated by 1.5x fold in mice receiving DOX+TRZ. This marker of apoptosis was attenuated by prophylactic treatment with either PER, EMPA, or EMPA+PER, to a level comparable with control mice. Finally, in DOX+TRZ treated mice, an increase in two oxidized phosphatidylethanolamine (OxPE) species was observed. Preliminary data demonstrates there is a possible trend in which prophylactic treatment with EMPA+PER attenuates these markers of lipid oxidation. Conclusion: In a chronic in vivo murine model of DOX+TRZ induced cardiotoxicity, the prophylactic administration of PER, EMPA or EMPA+PER was effective in preventing adverse cardiovascular remodeling, attenuating histopathological changes in cardiomyocyte structure, and improving markers of oxidative stress and apoptosis.